Synthesis of some 1,4-dihydropyridines under the microwave irradiation

Full text of DOI:10.1134/S1070363210020362

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 2, pp. 376–377. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © D.P. Khrustalev, A.A. Suleimenova, S.D. Fazylov, A.M. Gazaliev, K.A. Ayapbergenov, 2010, published in Zhurnal Obshchei Khimii,
2010, Vol. 80, No. 2, pp. 349–350.
LETTERS
TO THE EDITOR
Synthesis of Some 1,4-Dihydropyridines
under the Microwave Irradiation
D. P. Khrustalev, A. A. Suleimenova, S. D. Fazylov,
A. M. Gazaliev, and K. A. Ayapbergenov
Institute of Organic Synthesis and Coal Chemistry of the Republic Kazakhstan,
ul. Alikhanova 1, Karaganda, 100000 Kazakhstan
e-mail: khrustalev@bk.ru
Received May 12, 2009
DOI: 10.1134/S1070363210020362
More than 30 years the derivatives of 1,4-dihyd-
ropyridines class are widely used in medicine as cal-
cium channel blockers. Features of the structure and
unique action make these compounds irreplaceable for
treating hypertonic and cardiovascular diseases, preven-
tion and treatment of strokes [1]. However the des-
cribed in the literature convection synthesis approach
to 1,4-dihydropyridines have an essential drawback:
duration of the reaction [2–5].
We studied the synthesis method of the symmetric
1,4-dihydropyridines by the three-component reaction
of ammonia donor, ethyl acetoacetate, and aromatic
aldehydes under the microwave irradiation conditions:
CHO
R
H3C
O
MW
2
H2C
EtO
+
[NH3]
+
EtOOC
Me
COOEt
Me
O
R
N
H
R = Ph (I), 4-NO2C6H4 (II), CH3OС6Н4 (III).
In the reaction we used a stoichiometric ratio of
ethyl acetoacetate and the corresponding aldehyde. As
ammonia donors we used 25% ammonia aqueous
solution, ammonium acetate in acetic acid, and ammo-
nium carbonate. As evident from the method a, the
best results were obtained if the reaction with ammo-
nium acetate was carried out in acetic acid.
reaction mixture was recrystalled from ethanol. Yields
70% (I), 86% (II), 65% (III).
Method b. Into the flat-bottom flask of
thermostable glass (250 ml) was placed 5 ml of glacial
acetic acid, then was gradually added 15 ml of 25%
aqueous ammonia under stirring. Thereafter to the
reaction mixture were added 0.01 mol of the
corresponding aldehyde and 2.6 g (0.02 mol) of ethyl
acetoacetate. The reaction mixture was subjected to
microwave irradiation of 150 W for 5–10 min off and
on through each 1–2 min. The reaction progress was
monitored by TLC. The precipitate formed after the
reaction mixture cooling was recrystalled from
ethanol. Yields 68% (I), 83% (II), 70% (III).
Method a. Into the flat-bottom flask of thermo-
stable glass (250 ml) were placed 0.01 mol of the
corresponding aldehyde, 10 ml of 25% aqueous
ammonia, and 2.6 g (0.02 mol) of ethyl acetoacetate.
The reaction mixture was subjected to microwave
irradiation of 150 W for 5 min with off and on through
each 1–2 min. The precipitate formed after cooling the
376

SYNTHESIS OF SOME 1,4-DIHYDROPYRIDINES
377
Method c. Into the flat-bottom flask of thermostable
glass (250 ml) were placed 0.015 mol of the cor-
responding aldehyde, 2.6 g (0.02 mol) of ethyl
acetoacetate and 0.72 g (0.0075 mol) of ammonium
carbonate. The reaction mixture was subjected to
microwave irradiation of 150 W for 15–20 min off and
on through each 5 min. The reaction progress was
monitored by TLC. The precipitate formed after cool-
ing the reaction mixture was recrystalled from ethanol.
Yields 62% (I), 82% (II), 53% (III).
%: C 60.91; H 5.98. C19H22N2О6. Calculated, %: C
60.95; H 5.92.
4-(4-Methoxy)-2,6-dimethyl-3,5-dicarbomethoxy-
1,4-dihydropyridine (IIIc): mp 170–172°С. IR spec-
trum (KBr), ν, cm–1: 3365, 3096, 2950, 2838, 1680,
1
1653, 1265, 1131, 1049, 942, 745. H NMR spectrum
(DMSO-d5), δ, ppm: 2.33 s (6H), 3.65 s (6H), 3.75 s
(3H), 4.94 s (1H), 8.87 s (1H), 7.11–7.35 m (4H).
Found, %: C 65.31; H 6.40. C18H21NО5. Calculated,
%: C 65.24; H 6.39.
The IR spectra were recorded on a Nicolet 5700
1
REFERENCES
spectrophotometer (KBr). The Н NMR spectra were
registered on a Bruker DRX500 device (500.13 MHz).
1. Moiseev, V.S., Klin. Farmakol. i Terapiya, 2006, vol. 15,
4-Phenyl-2,6-dimethyl-3,5-dicarbethoxy-1,4-di-
hydropyridine (Ia): mp 145–146°С. IR spectrum, ν,
cm–1: 3324, 3060, 2982, 1688, 1647, 1487, 1050, 827,
no. 3, p. 45.
2. Kappe, C.O., Molecules, 1998, no. 3, p. 1.
3
Khrustalev, D.P., Trudy Mezhdunaronoi nauchno-prak-
ticheskoi konf. “Nauka i obrazovanie – vedushii faktor
strategii” (Prpc. Int. Conf. “Science and Education –
Fundamental Factor of Stratagt”), Karaganda, 2009,
p. 422.
1
703. H NMR spectrum (DMSO-d5), δ, ppm: 1.13 t
(6H), 2.50 s (6H), 4.00 s (4H), 4.85 m (1H), 8.7 s (1H),
7.25–7.35 m (5H). Found, %: C 69.25; H 7.11.
C19H23NO4. Calculated, %: C 69.28; H 7.04.
4. Saini, A., Kumar, S., and Sandhu, J.S., J. of Scientific &
4-(2-Nitrophenyl)-2,6-dimethyl-3,5-dicarboethoxy-
1,4-dihydropyridine (IIb): mp 120–122°С. IR spec-
trum (KBr), ν, cm–1: 3330, 3101, 2996, 2952, 2849,
Industrial Research., 2008, vol. 67, no. 2, p. 95.
5. Johnson, D.S. and Li, J.J., The Art of Drug Synthesis,
1
New Jersey: Wiley, 2007, p. 159.
1682, 1647, 1495, 1052, 829, 712. H NMR spectrum
6. Kappe, C.O., Angew. Chem. Int. Ed., 2004, no. 43,
(DMSO-d5), δ, ppm: 1.13 t (6H), 2.35 s (6H), 3.98 m
(4H), 5.1 s (1H), 7.25–7.31 m (4H), 9.1 s (1H). Found,
p. 6250.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 2 2010